Comparative study on the efficacy of Conbercept and Aflibercept in the treatment of neovascular age-related macular degeneration

This study compares the effectiveness of Conbercept and Aflibercept in treating neovascular age-related macular degeneration (nAMD). Conducted at the First Affiliated Hospital of Chongqing Medical University's Ophthalmology Department (May 2020–May 2023), this prospective study enrolled 159 nAMD patients. Participants were randomly divided into two groups: one receiving 0.5 mg Conbercept and the other 2 mg Aflibercept intravitreal injections. Over 12 months, the study, employing a Treat-and-Extend (T&E) regimen, assessed Best-Corrected Visual Acuity (BCVA), Central Retinal Thickness (CRT) changes and injection frequency. Of the 159 patients, 137 (149 eyes) completed the study. No significant age difference was found between the groups (P = 0.331). After 12 months, BCVA improved similarly in both groups (Conbercept: 52.8 ± 18.9, Aflibercept: 52.0 ± 19.7 letters; P = 0.820). CRT reduction was also comparable (Conbercept: 246.3 ± 82.8 µm, Aflibercept: 275.9 ± 114.3 µm; P = 0.079). Injection frequencies averaged 6.9 ± 0.7 (Conbercept) and 6.7 ± 0.7 (Aflibercept; P = 0.255). Subtype analysis revealed Type 1 MNV had higher baseline BCVA and lower CRT, with more frequent injections compared to other types. Both Conbercept and Aflibercept are clinically similar in efficacy for nAMD, with the T&E regimen proving therapeutically effective and potentially reducing patient costs. Anti-VEGF treatment efficacy varies across nAMD subtypes, indicating a potential benefit in tailored treatments for specific subtypes. Clinical trial registration number NCT05539235 (Protocol Registration and Results System).


Examination and enrolment
In this prospective study at the First Affiliated Hospital of Chongqing Medical University (May 2020 to May 2023), patients were randomly assigned to either the Conbercept or Aflibercept group.Inclusion criteria were age ≥ 50 years and confirmed nAMD via mydriatic slit lamp exam, OCT, OCTA, FFA, and ICGA, with no prior nAMD treatments.Only patients able to follow up for at least 12 months were included.Exclusion criteria encompassed coexisting fundus diseases (like retinal detachment, pathological myopia, proliferative diabetic retinopathy, glaucoma, retinal vascular diseases, macular membrane, macular hole), past internal eye surgery or fundus laser treatment, severe ocular trauma history, significant refractive medium clouding hindering fundus observation, and inability to maintain regular treatment follow-up or follow-up less than 12 months.
BCVA BCVA was recorded for all eligible patients pre-treatment, and at 1, 3, 6 months, and 1 year posttreatment, using the ETDRS chart for final assessment.
OCT and OCTA Examinations utilized the CIRRUS HD-OCT 5000 with pupil dilation to approximately 7mm.
FFA and ICGA Examinations used the Heidelberg Spectralis HRA angiography system from Germany.

Treatment
After routine preoperative exams and assessments, informed consent was obtained from patients and their families.Both groups underwent standardized intravitreal drug injections.According to different groups, the patients were given intravitreal injection of Conbercept (0.5mg) or Aflibercept ( 2 mg).
The patients in both groups adopted the T&E protocol 17 , namely, the initial treatment stage was three load injections, Conbercept (0. 5mg) or Aflibercept (2mg) was injected once every four weeks for three times, and the treatment interval was extended to eight weeks after that.Following the fourth injection, the subsequent treatment interval will be determined based on the patient's BCVA, CRT, OCT, and fundus photography.The intertreatment interval will not be shorter than 8 weeks and shall not exceed 16 weeks.Treatment interval extension: an extension of the treatment interval is warranted when the following conditions are concurrently satisfied: (1) Vision stability with a < 5-letter decrease in sequential BCVA assessments; (2) Retinal thickness stability, with CRT increment of < 50μm; (3) Absence of persistent intraretinal fluid (IRF) and subretinal fluid (SRF), or stable persistent retinal fluid over three consecutive visits, attributed to long-standing anatomical changes or fibrosis without active CNV; (4) No new neovascularization; and (5) No new macular hemorrhage.Treatment interval retention: the established interval may be upheld when all specified parameters are met: (1) Visual acuity decline .

Results
The study enrolled 159 patients (May 2020 to May 2023), including 79 patients in the Conbercept group and 80 patients in the Aflibercept group, with 137 (149 eyes) completing the 12-month follow-up, 82 eyes received Conbercept and 67 Aflibercept.9 participants in the Conbercept group and 13 in the Aflibercept group voluntarily withdrew from the study, citing personal reasons.Baseline characteristics (age, gender, BCVA, CRT, OCTA MNV classification) showed no significant differences between groups, detailed in Table 1.

BCVA
At 12 months, no significant differences in BCVA or mean changes were observed between groups, detailed data are shown in Fig. 1a and Table 2. 50.0% of Conbercept and 64.2% of Aflibercept patients showed > 5 letter BCVA improvement (Fig. 2).Type 1 MNV had a higher BCVA baseline (57.1 ± 16.0 letters) than other types (P < 0.05).At 12 months, no significant differences in mean changes were observed between four types, detailed data are shown in Table 3.After grouping all patients according to MNV subtype, an analysis was conducted on baseline BCVA and changes in BCVA (Fig. 1c, Fig. 1d, Table 3).At month-12, the proportion of patients with stable or improved vision in Conbercept group is higher than Aflibercept group, while the proportion of patients with reduced vision is lower than that Aflibercept group (Fig. 2).

CRT
During the 12-month treatment period, both groups of patients exhibited a continuous decrease in CRT compared to baseline levels (Fig. 1b).At the 1st and 6th months, the Conbercept group showed a significantly greater reduction in CRT compared to the Aflibercept group, as indicated in Table 3.After grouping all patients according to MNV subtype, an analysis was conducted on CRT baseline and changes in CRT (Fig. 1e,f, Table 3).At month-12 the CRT baseline for Type 1 MNV was 325.6 ± 128.1 µm, significantly lower than that of other types of MNV (P < 0.05)(Table 3).

Injection times
At the 12-month follow-up, the average number of intravitreal injections in the Conbercept group and the Aflibercept group, respectively, with no statistically significant difference between the two groups (p = 0.255).Detailed data of the intervals for the last injection are shown in Fig. 3b.

Postoperative complications
In this study, a total of 5 cases of subconjunctival hemorrhage were observed (4 cases in the Conbercept group and 1 case in the Aflibercept group).These cases did not receive any specific treatment, and the symptoms resolved spontaneously after observation.There were no postoperative complications such as elevated intraocular pressure, vitreous hemorrhage, intraocular inflammation, or retinal detachment observed in either group of patients.

Discussion
This study, the first prospective analysis over a year comparing Conbercept and Aflibercept in a real-world context, reveals their similar efficacy and safety for nAMD.With no significant differences in injection frequency or safety, both are viable nAMD treatment options.
Conbercept, a 143 kDa fusion protein, combines VEGFR1Ig2, VEGFR2Ig3, and VEGFR2Ig4 of human VEGF receptors with IgG1 Fc 10 , binding all VEGFA, VEGF-B, VEGF-C, and PlGF subtypes 18,19 .Aflibercept, at 115 kDa, fuses VEGFR1Ig2 and VEGFR2Ig3 with IgG1 Fc 20,21 , targeting VEGF-A, VEGF-B, and PlGF 22 .In rabbit vitreous, Conbercept has a 4.2-day half-life, longer than Aflibercept's 3.63 days 23,24 .Conbercept's unique inclusion of VEGFR2's fourth domain enhances VEGF affinity and lowers extracellular matrix adhesion, potentially boosting its anti-angiogenic effectiveness 9 .Despite these differences, comparative studies in nAMD show no clear superiority of either drug in improving visual acuity, anatomical outcomes, or treatment frequency.In studies utilizing the 3 + T&E regimens (injection intervals extended or shortened by 4 weeks), the COCOA study, a pioneering multicentric prospective Chinese trial, compared Conbercept 3 + T&E (treatment intervals adjusted by 4 weeks) against a 3 + PRN regimen in 501 patients.By week 48, more than half of the participants had received 6 or fewer injections.In the 3 + T&E cohort, visual acuity improved by an average of 8.6 letters, with about 62% of patients having ≥ 12-week intervals and 42% extending to 16 weeks 20 .The ALTAIR Study, administering 2 mg Aflibercept intravitreally, observed an average improvement of 8.4 letters in visual acuity at 52 weeks and an average of 6.9 injections over 12 months, accompanied by a mean CRT reduction of 126.1 μm.Approximately 49.6% of the patients in this study extended the final injection interval to ≥ 12 weeks, and 40.7% to 16 weeks 25  www.nature.com/scientificreports/evaluating Aflibercept, the comparative assessment in terms of BCVA improvement, CRT reduction, and injection frequency did not demonstrate clear dominance of either treatment 10,26,27 .Drug clearance from the vitreous hinges on molecular size.Due to their larger molecular weight, these drugs minimally penetrate the blood-ocular barrier, ensuring high selectivity and few systemic adverse reactions, confirming their safety.This study finds no significant difference between the two drugs in efficacy, injection frequency, or adverse reactions, consistent with previous research.While Conbercept's additional structural domain might suggest greater efficacy, this doesn't necessarily translate to clinical significance.As AMD is influenced by various factors, patients' responses to anti-VEGF treatments can vary, with some experiencing reduced effectiveness over time.Notably, despite these treatments, AMD-related blindness incidences continue to increase annually 28 .
A U.S. study of 98,821 AMD eyes undergoing intravitreal anti-VEGF therapy showed a general visual acuity decline over four years 29 .This decrease is partly due to these treatments' inability to address factors like age, genetics, and environmental and cardiovascular influences.AMD's Geographic Atrophy (GA) grows about 0.33 mm/year, with a 38% incidence rate five years after starting anti-VEGF therapy 30 .Normally, ocular VEGF is essential for RPE survival and choroidal endothelial cell function 31 , so anti-VEGF treatments might increase GA risk 32 , possibly diminishing or even worsening visual acuity over time.This could explain the converging efficacy in long-term therapy.However, studies suggest no direct link between anti-VEGF dosing or injection frequency and macular atrophy rates in nAMD 33 .
After a year, visual acuity gains in both groups were 4.18 ± 8.80 and 5.25 ± 11.23 letters, lower than previous CATT study results.
Contributing factors include lower baseline visual acuity (Conbercept: 48.59 ± 18.33, Aflibercept: 46.79 ± 14.70 letters) compared to the 2012-2015 average of 53.1 letters 29 .This suggests more advanced disease at treatment onset, typically offering limited visual improvement.Also, about 46% of patients had Type 2 MNV, which, despite initial responsiveness to treatment, often leads to fibrotic scarring, potentially impairing long-term vision 34 .The   high proportion of Type 2 cases may limit overall BCVA improvement.Furthermore, the T&E regimen in this study, with 4-week extension and shortening intervals (minimum 8 weeks, maximum 16 weeks), lacked adaptability for patients needing more frequent treatments, potentially leading to lesser visual improvement and not fully addressing specific needs.The fixed interval scheme could explain why more patients extended their last treatment interval to ≥ 12 weeks compared to prior studies.In a subtype-based analysis, Type 1 neovascularization patients, with higher initial BCVA, needed more frequent injections but didn't show significant visual improvement over other types.Typically, Type 1 patients have higher baseline BCVA and better vision improvement, requiring more treatments 35 .This MNV, located beneath the RPE, preserves visual acuity by not damaging the RPE and maintaining its barrier and transport functions, reflected in this study's lower average CRT for Type 1.However, the deeper neovascularization location reduces the concentration of anti-VEGF medication reaching it to just 11.9% of that in the vitreous cavity 23 .Consequently,  maintaining anti-VEGF treatment efficacy over time is challenging, and patients with this type often experience recurrent episodes, needing more injections for effective management.In this study, Type 2 neovascularization incidence (51.7%) was higher than in past CATT studies (19.2-23.7%) 36.This could reflect regional differences due to the study's single-center nature.Type 2 patients had lower baseline BCVA but needed fewer treatments, and their visual improvement was not significantly inferior to other subtypes.
Type 2 MNV, penetrating and located above the RPE, often presents with poorer vision.Yet, its accessibility to anti-VEGF medications leads to better treatment response and fewer injections 37 , however, there are studies indicating that Type 2 neovascularization may require a higher frequency of treatment interventions 35 .This increased treatment frequency in Type 2 patients could be attributed to their higher susceptibility to fibrotic scarring 38 , it can impede improvements in visual acuity and the efficacy of treatment, potentially leading to more frequent injections in clinical practice.The prevalence of Type 2 in our study may have influenced average baseline BCVA, BCVA improvement, CRT reduction, and injection numbers.Type 3 patients, typically with poorer baseline vision, required more frequent injections, and experienced BCVA decline by 12 months.This subtype is characterized by significant RPE damage, with 6 patients (50%) already exhibiting atrophic changes in the macular RPE at the onset of treatment.By the 12th month, 2 more patients developed macular RPE atrophy.Previous studies have also indicated a higher propensity for Geographic Atrophy (GA) in patients with Type 3 neovascularization 30 .Mixed subtype patients had the poorest baseline BCVA and needed fewer injections, though the small sample size limits generalization.Considering these subtype differences, tailored treatments are essential, especially for unstable types like 1 and 3, where shorter interval dosing might be more effective.Future therapies should thus be subtype-specific for nAMD.

Limitations
This single-center study may limit the generalizability of population characteristics.Its small sample size, especially for Type 3 and mixed subtypes, could bias data analysis.The one-year follow-up might be insufficient for comparing long-term drug efficacy.Fixed treatment intervals, not tailored to patient conditions, may have affected anti-VEGF therapy effectiveness.Additionally, many patients had poor baseline visual acuity, suggesting advanced disease stages, which could influence OCT and OCTA subtype-based observations and outcomes. https://doi.org/10.1038/s41598-024-62536-8

Figure 1 .
Figure 1.(a) Mean BCVA (letter Score) at baseline and at each follow-up time until month 12 in the two groups; (b) Mean CRT (μm) at baseline and at each follow-up time until month 12 in the two group; (c) BCVA baseline (letter Score) of four types of MNV; (d) BCVA variation from month-12 to baseline (letter Score) of four types of MNV; (e) CRT baseline of four types of MNV; f:CRT variation from month-12 to baseline (letter Score) of four types of MNV."**" means P < 0.01, "***" means P < 0.001.

Figure 2 .
Figure 2. Classifying according to the change in BCVA letter score.

Table 2 .
Comparison the difference of BCVA letter score and CRT between the two groups.BCVA, bestcorrected visual acuity; SD, standard deviation.CRT, central retinal thickness.Significant values are in bold.